Cell signaling molecules, such as hormones, neurotransmitters and cytokines, mediate cell--cell communication by acting through specific receptors on the plasma membrane or in the cytoplasm of target cells to ultimately transduce the signal into a cellular response. A delicate balance between activation and termination of signal transduction pathways is critical to maintaining homeostasis of the cell and organism.
Tyrosyl-phosphorylation regulates cell proliferation, migration and differentiation in complex biological processes such as embryonic development. Following binding of a signaling molecule to a cell surface receptor, tyrosine phosphorylation of target substrates, including some receptors, takes place by the activation of protein-tyrosine kinases. Termination of the signal is the result of activation of protein-tyrosine phosphatases and accompanying de-phosphorylation of tyrosine residues on the target substrates. Protein tyrosine phosphatases can have signal-enhancing or signal-attenuating properties.
SH2-domain-containing protein tyrosine phosphatases (e.g., SHP-1, SHP-2, and corkscrew in Drosophilia melanogaster) are a family of protein tyrosine phosphatases that share a common structure consisting of two SH2 ("S"rc "H"omology-2) domains, a protein tyrosine phosphatase catalytic domain containing the conserved I/VHCxAGxxR(S/T)G SEQ ID NOS: 1-70 amino acid sequence and a carboxy-terminal extension (Neel, B. G., Sem. Cell Biol. 4:419-432 (1993); Perkins, L. A., et al., Dev. Biol. 180:63-81 (1996); Neel, B. G., et al., Curr. Op. Cell Biol. 9:193-204 (1997)) (FIG. 1). The two SH2 domains are referred to as amino-(N-SH2) and carboxy-SH (C-SH2) domains relative to their position to the amino-terminus of the phosphatase protein.
Protein-tyrosine phosphatases, including SH2-containing phosphatases, are highly conserved among eukaryotes from such diverse species as mammals, including humans, to yeast and Xenopus. Mutations and altered expression of protein-tyrosine phosphatases have been implicated in neoplastic diseases and developmental abnormalities (Tonks, N. K., et al., Cell 87:365-368 (1996); Neel, B. G., et al., Curr. Op. Cell Biol. 9:193-204 (1997); Li, J. et al., Science 275:1943-1947 (1997)).
Thus, due to their widespread phylogenetic distribution and importance in the homeostasis of organisms a clearer understanding of the role of structural determinants in the catalytic activity of SH2-containing protein tyrosine phosphatases in cells and developmental events (such as embryonic shaping, patterning and organogenesis) can provide new and meaningful insights into their function and their role in disease.